Alzheimer's disease (“AD”) is a neurodegenerative disorder with an estimated worldwide prevalence of over eighteen million people, and is predicted to increase with an increasing elderly population. AD is characterized by cognitive deficits and memory impairment, and there is currently no cure for this disease. Several genetic, age, demographic and environmental factors are linked to AD pathophysiology. Chapman et al., 2001, Trends in Genet. 17, 254-261; Cummings et al., 1998, Neurology, 51, S2-17; Doraiswamy et al., 2002, Bio. Sci. Med. Sci., 57, M173-M177. Two pathological characteristics are observed in AD patients at autopsy: extracellular plaques and intracellular tangles in the hippocampus, cerebral cortex, and other areas of the brain essential for cognitive function. Plaques are formed mostly from the deposition of amyloid beta (“Aβ”), a peptide derived from amyloid precursor protein (“APP”). Filamentous tangles are formed from paired helical filaments composed of neurofilament and hyperphosphorylated tau protein, a microtubule-associated protein.
The main clinical feature of AD is a progressive cognitive decline leading to memory loss. Memory dysfunction involves impairment of learning new information which is often characterized as short-term memory loss. In the early (mild) and moderate stages of the illness, recall of remote well-learned material may appear to be preserved, but new information cannot be adequately incorporated into memory. Disorientation to time is also closely related to memory disturbance.
Language impairments are also a prominent part of AD. These are often manifest first as word finding difficulty in spontaneous speech. The language of the AD patient is often vague, lacking in specifics and may have increased automatic phrases and clichés. Difficulty in naming everyday objects is often prominent. Complex deficits in visual function are present in many AD patients, as are other focal cognitive deficits such as apraxia, acalculia and left-right disorientation. Impairments of judgment and problem solving are frequently seen.
Non-cognitive or behavioral symptoms are also common in AD. Personality changes are commonly reported and range from progressive passivity to marked agitation. Patients may exhibit changes such as decreased expressions of affection, depressive symptoms, anxiety, and psychosis. In some cases, personality changes may predate cognitive abnormality.
Currently, the primary method of diagnosing AD involves taking detailed patient histories, administering memory and psychological tests, and ruling out other explanations for memory loss, including temporary (e.g., depression or vitamin B12 deficiency) or permanent (e.g., stroke) conditions. Under this approach, AD cannot be conclusively diagnosed until after death, when autopsy reveals the disease's characteristic amyloid plaques and neurofibrillary tangles in a patient's brain. In addition, clinical diagnostic procedures are only helpful after patients have begun displaying significant, abnormal memory loss or personality changes. By then, a patient has likely had AD for years. There is therefore a need for other methods of diagnosing and aiding diagnosis of AD.
Mass spectrometers are often coupled with chromatography systems in order to identify and characterize eluting species from a test sample. In such a coupled system, the eluting solvent is ionized and a series of mass spectrograms are obtained. In some cases, liquid chromatography is coupled with tandem mass spectrometry (LCMS2) for better analysis of test samples. See, e.g., U.S. Pat. No. 7,009,174; Jansen et al., J. Chromatography, 830:196-200 (2006).
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